The impact of cineole treatment timing on common cold duration and symptoms: Non-randomized exploratory clinical trial.

INTRODUCTION: Common cold (CC) symptoms arise from an inflammatory response treatable with cineole and generally peak within two days, which complicates research implementation. We therefore explored the benefits of early cineole administration with enrolment of participants prior to CC onset. METHODS: Out of 522 adults enrolled in our phase IV, open-label, non-randomized, exploratory clinical trial (EudraCT No. 2020-000860-51), 329 developed a CC and used 200 mg cineole (Soledum®, CNL-1976) t.i.d. for max. 15 (± 2) days. Primary endpoint was burden of disease based on the Wisconsin Upper Respiratory Symptom Survey (WURSS-11). RESULTS: Comparing three strata based on time to treatment (≤ 12 h, > 12 to ≤ 24 h and > 24 h), earliest treatment resulted in lowest AUC-WURSS (Spearman correlation coefficient of 0.36) and reduced the overall burden of disease by 38% (p < 0.0001). Earlier and lower symptom severity peak resulted, with shorter time to remission (average 8.9 vs. 10.7 days with latest treatment initiation, p < 0.05), and higher and faster recovering quality of life (p < 0.05). Tolerability was mostly rated as "very good", with adverse events of suspected causal relationship reported in 4.3% of participants. CONCLUSIONS: Early intervention shows clinical benefits relevant for the effective treatment of CC with cineole.

Enhanced Blood Supply Through Lower Body Negative Pressure During Slow-Paced, High Load Leg Press Exercise Alters the Response of Muscle AMPK and Circulating Angiogenic Factors.

Lower body negative pressure (LBNP) is an established method of simulating the gravitational effects of orthostasis on the cardiovascular system during space flight or at supine body position on Earth. We hypothesized that LBNP added onto leg press exercise would promote leg muscle perfusion, stimulate oxygen consumption, and modify acute molecular responses. Eighteen subjects performed fifteen slow-paced concentric (4 s) and eccentric contractions (4 s) without or with 40 mmHg LBNP. Force corresponding to 6% of the one-repetition maximum (1-RM) at knee flexion gradually increased to 60% 1-RM within the first half of the range of motion, thereafter remaining constant. AMPK and P-AMPK protein expression was determined in biopsies of vastus lateralis. Venous blood samples were used to measure angiogenic factors. Physiological responses to LBNP included an elevated EMG amplitude, higher heart rate and doubling of the cardiac output compared to control (p < 0.001). Muscle total hemoglobin was increased by around 20 µmol/l vs. control (p < 0.001), accompanied by decreasing tissue oxygen saturation and elevated oxygen uptake (p < 0.05). MMP-2 levels were reduced, and the ratio of P-AMPK to AMPK elevated after exercise with LBNP (p < 0.05). MMP-9 similarly increased in both groups, whereas endostatin was only elevated in the control group (p < 0.05). Our results indicate facilitated peripheral blood supply and higher oxygen exploitation leading to activation of the energy sensor AMPK and differential regulation of angiogenic factors involved in muscle tissue remodeling and capillary growth. Simulating orthostasis with LBNP might promote beneficial structural adaptations of skeletal muscles during resistance exercise and contribute to future exercise countermeasures achieving increased muscle strength and endurance during space flight.

Lower body negative pressure enhances oxygen availability in the knee extensor muscles during intense resistive exercise in supine position.

PURPOSE: During exercise in supine posture or under microgravity in space, the gravity-dependent component of local blood pressure in leg muscles at upright posture can be simulated by lower body negative pressure (LBNP). We hypothesized that during resistive exercise LBNP favors oxygen availability in lower extremities, benefiting energy levels and performance of working muscles. METHODS: In permutated crossover design, nine subjects performed a series of fifteen slow-paced concentric (4 s) and eccentric contractions (4 s) without or with 40 mmHg LBNP and 4 s pause between repetitions. The force at knee flexion was 6% of the one repetition maximum (1-RM) and gradually increased to 60% 1RM in the first half of the individual range of motion, subsequently remaining constant until full extension. RESULTS: During the low force periods of continuous exercise, LBNP enhanced the refill of capillary blood measured by near infrared spectroscopy, amplifying the increase of total haemoglobin by about 20 µmol/l (p < 0.01) and oxyhaemoglobin by about 10 µmol/l (p < 0.01). During continuous exercise, LBNP induced a trend towards a lower EMG increment. This LBNP effect was not found when the periods of low forces at knee flexion were extended by 4 s pauses. Increased respiratory oxygen uptake (+ 0.1 l/min, p < 0.05) indicated overall enhanced muscle energy turn-over. CONCLUSIONS: Our results suggest stimulation of oxidative metabolism through LBNP enables working muscles to meet the energy demands of intense exercise. Further research is needed on the consequences for energy metabolism and the molecular control of growth and differentiation.

Loss of PINK1 impairs stress-induced autophagy and cell survival.

The mitochondrial kinase PINK1 and the ubiquitin ligase Parkin are participating in quality control after CCCP- or ROS-induced mitochondrial damage, and their dysfunction is associated with the development and progression of Parkinson's disease. Furthermore, PINK1 expression is also induced by starvation indicating an additional role for PINK1 in stress response. Therefore, the effects of PINK1 deficiency on the autophago-lysosomal pathway during stress were investigated. Under trophic deprivation SH-SY5Y cells with stable PINK1 knockdown showed downregulation of key autophagic genes, including Beclin, LC3 and LAMP-2. In good agreement, protein levels of LC3-II and LAMP-2 but not of LAMP-1 were reduced in different cell model systems with PINK1 knockdown or knockout after addition of different stressors. This downregulation of autophagic factors caused increased apoptosis, which could be rescued by overexpression of LC3 or PINK1. Taken together, the PINK1-mediated reduction of autophagic key factors during stress resulted in increased cell death, thus defining an additional pathway that could contribute to the progression of Parkinson's disease in patients with PINK1 mutations.

Loss of mitochondrial peptidase Clpp leads to infertility, hearing loss plus growth retardation via accumulation of CLPX, mtDNA and inflammatory factors.

The caseinolytic peptidase P (CLPP) is conserved from bacteria to humans. In the mitochondrial matrix, it multimerizes and forms a macromolecular proteasome-like cylinder together with the chaperone CLPX. In spite of a known relevance for the mitochondrial unfolded protein response, its substrates and tissue-specific roles are unclear in mammals. Recessive CLPP mutations were recently observed in the human Perrault variant of ovarian failure and sensorineural hearing loss. Here, a first characterization of CLPP null mice demonstrated complete female and male infertility and auditory deficits. Disrupted spermatogenesis already at the spermatid stage and ovarian follicular differentiation failure were evident. Reduced pre-/post-natal survival and marked ubiquitous growth retardation contrasted with only light impairment of movement and respiratory activities. Interestingly, the mice showed resistance to ulcerative dermatitis. Systematic expression studies detected up-regulation of other mitochondrial chaperones, accumulation of CLPX and mtDNA as well as inflammatory factors throughout tissues. T-lymphocytes in the spleen were activated. Thus, murine Clpp deletion represents a faithful Perrault model. The disease mechanism probably involves deficient clearance of mitochondrial components and inflammatory tissue destruction.